Closed-loop non-invasive stimulation for improving brain and mental health

Recent breakthroughs in neuromodulation, neuroimaging, and machine learning offer the potential for development of new treatments and optimising and personalising existing treatments to tackle neuropsychiatric conditions that have a huge personal, social, and economic impact. While many neuropsychiatric conditions are currently treated with a combination of medications and psychosocial approaches, a significant proportion of patients show poor response to treatment. For instance, one-third of patients with depression and a quarter of patients with a first episode of psychosis show poor response to existing treatments. Besides, cognitive impairments, that predict the quality of life for patients with neuropsychiatric conditions, are largely unresponsive to current treatment approaches. Furthermore, side effects from medications and reduced concordance with medications remain a significant issue. Stimulation of distinct regions of the brain (‘neuromodulation’) offers a potential route to new treatments for patients who respond poorly to current—mainly pharmaceutical—interventions or suffer from significant, sometimes intolerable, side-effects. However, the effects of neuromodulation are often inconsistent. Understanding how neuromodulation affects brain microstructure, circuits and dynamics is key for efficacious, personalised treatment to improve cognitive function. As a starting point, Nottingham University led a large-scale trial on neuromodulation interventions for medically intractable depression (Morriss et al., Nature Medicine, 2024). While this study showed significant long-term improvements after 26+ weeks, several sessions were needed and not all patients showed consistent improvements. While there is a clear clinical need to have alternative interventions such a neuromodulation, only few conditions can currently be treated, and many neuromodulation approaches are invasive (e.g. implants for Parkinson’s disease or Obsessive-Compulsive Disorder). Another aspect that limits current approaches, and an aspect we want to focus on here, is that they are open-loop. Open-loop stimulation is applying stimulation irrespective of ongoing brain activity. We already observed improved brain function after open-loop magnetic stimulation in depression patients and improved cognition after focused ultrasound stimulation for healthy participants. Closed-loop stimulation instead times pulses to coincide with specific brain activity patterns. Within this programme, we will test whether closed-loop stimulation can increase effect sizes. Such an advancement will shorten the number of sessions that are needed for clinical applications, could lead to more consistent results across individuals, and might broaden the scope of brain stimulation interventions across brain and mental health conditions. Within this MRC programme grant, we will (1) test the effect of closed-loop ultrasound or magnetic stimulation, (2) observe biological changes through EEG and magnetic resonance spectroscopy, (3) develop computational/machine learning models to predict stimulation outcomes, and (4) test cognitive and motor function improvements in patients with psychiatric (schizophrenia, bipolar disorder, depression) and neurological (tics disorder) disorders. To achieve these goals, we apply approaches from neuroimaging, brain stimulation, cognitive neuroscience, and computational neuroscience/neuroinformatics. Moreover, our team includes experts in schizophrenia, depression, and Tourette’s syndrome to support proof-of-principle pilot studies in patients. In summary, with neuromodulation we aim to achieve longer-term changes associated with improvement in difficult-to-treat symptoms, functioning and quality of life whilst reducing the frequency and severity of any adverse effects. Our programme grant will build on our previous work to shift our understanding of the effect of stimulation and how it can be developed into a personalised closed-loop intervention.